The present invention relates to anhydrous 18F-radiolabeled fluorinating agents and methods for their production and use.
Nuclear medicine uses a variety of radionuclides incorporated into specific compounds for diagnostic imaging and therapeutic applications such as positron emission tomography and cancer treatment. Positron emission tomography (PET) is a non-invasive, functional and metabolic imaging technique by which the decay of a radioactive drug, for example, a radiopharmaceutical or radiotracer, allows one to image body tissues in humans and animals. To conduct a PET scan, a short-lived radioactive tracer isotope that has been incorporated into a metabolically active molecule is administered to a patient or subject. Following a waiting period where the radiotracer becomes concentrated into the tissue(s) of interest, the patient or subject is placed in an imaging scanner. The decay of the radiotracer is monitored by detecting the gamma ray emission resulting from an annihilation event in which a positron collides with an electron giving rise to two photons. Since two gamma rays are produced from each decay event, and because these rays are emitted at almost 180° angles to one another, the location of the radiotracer drug molecule may be ascertained and a three dimensional image of the tissue distribution of the radiotracer drug molecule may be reconstructed. Therapeutic applications use radiopharmaceuticals that deliver a radioactive isotope to a target tissue. As the radioactive isotope decays, the tissue is destroyed.
Synthesis of the radionuclide is a critical component in the manufacture of the finished radiotracer or radiopharmaceutical. One commonly used radioisotope for PET is a radioisotope of fluorine, 18F. The 18F radioisotope of fluorine decays with a half life of about 110 minutes. One method for generating 18F is by bombarding an 18O labeled water target with a proton beam from a cyclotron causing a (p,n) reaction in the 18O to produce 18F as a labeled hydrofluoric acid (HF). The radioactive fluoride ion (18F−) must then be rapidly incorporated into a drug molecule by a series of chemical reactions, then purified and administered to a patient or subject. Speed and efficiency are essential for preparing radiopharmaceuticals and radiotracers because they dictate the amount of radioactive isotope available in the radiopharmaceutical or radiotracer and, consequently, the quality of the image and the radiotracer dose. Currently, fluorinated radiopharmaceuticals or radiotracers are prepared most often from 18F salts, such as potassium fluoride, which are generally produced in a hydrated state after the nuclear reaction. Hydrated fluoride salts, however, are only weakly reactive. Because of the weak reactivity of hydrated fluoride salts, relatively harsh reaction conditions (for example, high temperatures, high boiling point solvents) and relatively expensive cation sequestering agents are employed to incorporate 18F into a radiopharmaceutical or radiotracer drug intermediate. Additionally, these salts are often “activated” by addition of cryptands, such as Kryptofix 222, to complex the cation and to boost fluoride nucleophilicity. Even using these harsh conditions and expensive agents, some classes of desirable drugs cannot be prepared using 18F within the extremely short time frame required for these drugs to be useful. Accordingly, there is a need for preparing 18F-labeled radiopharmaceuticals and radiotracers more efficiently and rapidly than current techniques allow.
U.S. Pat. No. 7,592,486 describes a novel method for producing anhydrous organic fluoride salts and reagents and novel anhydrous organic fluoride salts and reagents. Previously, there was a belief among those skilled in the art that it was unlikely that pure, anhydrous tetraalkylammonium fluoride salts had ever been produced in the case of ammonium ions susceptible to E2 eliminations. The method of U.S. Pat. No. 7,592,486 involves a one-step reaction carried out at low temperatures (−35° C.) to room temperature and uses a fluorinated compound with a large number of fluorine atoms per unit weight, for example, hexafluorobenzene, octafluoronaphthalene, pentafluorobenzonitrile, pentafluoropyridine, and decafluorobiphenyl, to synthesize an anhydrous fluoride salt. The object of the method and the organic fluoride salts and reagents described in U.S. Pat. No. 7,592,486, therefore, is to produce truly anhydrous organic fluoride salts.